Most acute myeloid leukemia (AML) is lethal due to relapse that is typically resistant to 2nd or 3rd-line treatments. How et al., Blood Cancer J., 3:e116 (2013). Why do 1st-line treatments select for AML cells somehow resistant to subsequent treatments targeting different molecules? One reason is that treatments overlap in final pathways of action despite distinct proximal molecular targets: current treatments induce apoptosis (cytotoxicity), via stress applied upstream of p53, the master transcription factor (TF) regulator of apoptosis. In some AML cases, p53-system attenuation by genetic alterations to TP53, MDM2/4 etc. subverts this common apoptotic intent, causing resistance in vitro and clinically, as demonstrated. Wong et al., Nature, 518(7540):552-5 (2015). The same treatments destroy normal hematopoietic stem cells (HSC) with intact p53, causing substantial toxicities including death. Brennig et al., Cytotherapy, 14(4):451-60 (2012).
What is needed therefore is not just new treatments, but treatments that use pathways other than p53/apoptosis for cell cycle exits. Differentiation, not apoptosis, is the p53-independent pathway normally terminating myeloid precursor proliferation (billions of cells daily), and myeloid differentiation failure defines and diagnoses AML and a variety of other types of cancer. Two drugs, retinoic acid (ATRA) and arsenic trioxide, are FDA-approved for non-cytotoxic differentiation-restoring treatment of a rare sub-type of AML, acute promyelocytic leukemia (APL), and have transformed APL from worst to best in AML outcomes. Smith et al., Blood Reviews, 25(1):39-51 (2011); Hu Z, Saunthararajah Y., Blood, 119(9):2177-9 (2012). However, while ATRA and arsenic are strikingly curative, they are only effective for treating the very rare AML sub-type APL, since both agents specifically interact with the fusion protein PML-RARA that is unique to this leukemia.
Although conventional cytotoxic treatments for AML can have differing proximal actions, e.g., topoisomerase inhibition (daunorubicin) or termination of DNA chain synthesis (cytarabine), a final common pathway converges onto p53 (TP53), a master regulator of apoptosis (cytotoxicity). Kinzler K W, Vogelstein B., N Engl J Med., 331(1):49-50 (1994). As such, TP53 mutation/deletion is associated with resistance to treatments in vitro (Yin et al., Exp Hematol., 34(5):631-41 (2006)) and in vivo. TP53-mutated AML treated with daunorubicin and/or cytarabine had a response rate of 33% compared to 81% for TP53 wild-type AML (Wattel et al., Blood, 84(9):3148-57 (1994)), and chemotherapy has been shown to select for TP53 mutated AML sub-clones at relapse. Wong et al., Nature, 518(7540):552-5 (2015). Even if TP53 itself is not mutated, alterations in other key p53-system genes are frequent, e.g., gains in MDM4, which inactivates p53, are very common in highly chemorefractory sub-types of AML. Toledo F, Wahl G M, Nat Rev Cancer, 6(12):909-23 (2006). Meanwhile, cytotoxic treatments damage residual normal hematopoietic stem cells (HSC) and stroma, causing significant toxicities including fatal exacerbations of low blood counts in as many as 29% of patients treated. Roberts et al., Leukemia research, 39(2):204-10 (2015). Damage to normal stem cells is especially a problem in treating myeloid malignancies, where residual normal HSC are needed to reverse the low blood counts that are the cause of morbidity and death. Mandelli et al., European journal of cancer, 27(6):750-5 (1991). To spare normal HSC, treatments should exploit a difference between normal HSC and AML-initiating cells (leukemia stem cells).